EP0540574A1 - Peptides anticoagulants. - Google Patents

Peptides anticoagulants.

Info

Publication number
EP0540574A1
EP0540574A1 EP91913182A EP91913182A EP0540574A1 EP 0540574 A1 EP0540574 A1 EP 0540574A1 EP 91913182 A EP91913182 A EP 91913182A EP 91913182 A EP91913182 A EP 91913182A EP 0540574 A1 EP0540574 A1 EP 0540574A1
Authority
EP
European Patent Office
Prior art keywords
glu
peptide
phe
asp
pro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP91913182A
Other languages
German (de)
English (en)
Other versions
EP0540574B1 (fr
EP0540574A4 (fr
Inventor
John L Krstenansky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharmaceuticals Inc
Original Assignee
Merrell Dow Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merrell Dow Pharmaceuticals Inc filed Critical Merrell Dow Pharmaceuticals Inc
Publication of EP0540574A1 publication Critical patent/EP0540574A1/fr
Publication of EP0540574A4 publication Critical patent/EP0540574A4/en
Application granted granted Critical
Publication of EP0540574B1 publication Critical patent/EP0540574B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/815—Protease inhibitors from leeches, e.g. hirudin, eglin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to novel peptides which are useful anticoagulant and antiplatelet agents.
  • Anticoagulants are useful therapeutic agents in the pharmacological treatment of, for example, acute deep venous thrombosis, pulmonary embolism, acute arterial embolization of the extremities, myocardial infarction, and disseminated intravascular coagulation.
  • Prophylactic administration of anticoagulants is believed to prevent a recurrence of embolism in patients with rheumatic or arteriosclerotic heart disease and to prevent certain thromboembolic complications of surgery.
  • Administration of anticoagulants has also been indicated in the treatment of coronary artery and cerebrovascular disease. Arterial thrombosis, particularly in arteries supplying the heart muscle and brain, is a leading cause of death.
  • Hirullin P18 is a 61-amino acid hirudin-related protein having potent antithrombin activity. Similar to hirudin, it contains a highly acidic C-terminus of significantly different sequence from any other known hirudin variant. The C-terminal fragment acetyl-hirullin P18 40-61 has an antithrombin potency similar to that of acetyl- desulfatohirudin 45-65 . While applicant has discovered that certain amino acids residues of the native sequence are critical to maintaining the antithrombin activity of the fragment, other residues have been found to be less
  • hirullin P18 54-61 from hirudin 59-65 suggest a different mode of interaction with thrombin. Nevertheless, the C-terminal functional domain represented by hirullin P18 50-61 appears to be comparable to hirudin 55-65 in terms of its binding to thrombin and its functional role in the protein.
  • a 1 is a bond or is a peptide fragment
  • a 2 is a bond or is a group of the formula
  • n is an integer of from
  • a 3 is Phe, SubPhe, ⁇ -(2- and 3-thienyl)alanine, ⁇ -(2-and 3-furanyl)alanine, ⁇ -(2-, 3-, and
  • a 4 is a bond or is a group of the formula
  • n is an integer of
  • a 5 is any amino acid
  • a 6 is Tyr, Trp, Phe, Leu, Nle, Ile, Val, Cha and Pro;
  • a 7 is Pro, Ser, Ala, and Thr;
  • a 8 is Tyr, tyr, Trp, trp, Phe, phe, Leu, leu,
  • a 9 is any amino acid
  • a 10 is any amino acid
  • a 11 is Tyr, Trp, Phe, Leu, Nle, Ile, Val, Cha and Pro;
  • a 12 is a bond or is a peptide fragment
  • Y is a carboxy terminal residue selected from OH, C 1 -C 6 alkoxy, amino, mono- or di-(C 1 -C 4 ) alkyl substituted amino, or benzylamino; or a pharmaceutically acceptable salt thereof are useful anticoagulant agents.
  • Alkyl group and the alkyl portion of an alkoxy group is taken to include straight, branched, or cyclic alkyl groups, for example, methyl, ethyl, propyl, isopro- pyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, sec-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl and
  • acyl group of from 2 to 10 carbon atoms is taken to include straight, branched, cyclic, saturated and unsaturated acyl groups having 1 or 2
  • a halogen group is a fluoro, chloro, bromo or iodo group.
  • any amino acid as used herein includes the naturally occurring amino acids as well as other "non-protein" ⁇ -amino acids commonly utilized by those in the peptide chemistry arts when preparing synthetic analogs of naturally occurring peptides.
  • the naturally occurring amino acids are glycine, alanine, valine, leucine,isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, ornithine, and lysine.
  • non-protein ⁇ -amino acids are norleucine, norvaline, alloisoleucine, homoarginine, thiaproline, dehydroproline, hydroxyproline (Hyp), homoserine, cyclohexylglycine (Chg), ⁇ -amino-n-butyric acid (Aba), cyclohexylalanine (Cha), aminophenylbutyric acid (Pba), phenylalanines substituted at the ortho, meta, or paraposition of the phenyl moiety with one or two of the following, a (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halogen, or nitro groups or substituted with a methylenedioxy group, ⁇ -2- and 3-thienylalanine, ⁇ -2- and 3-furanylalanine, ⁇ -2-, 3-, and 4-pyridylalanine, ⁇ -(benzothienyl-2
  • Y is either Y 2 or Y 4 and Z is either Z 2 or Z 4 as defined above and p, q, and r are each an integer of from 1 to 5 and wherein R is a hydrogen or a (C 1 -C 4 )alkyl group.
  • lipophilic amino acid includes Tyr, Phe, Leu, Nle, Ile, Val, His and Pro.
  • the natural amino acids with the exception of glycine, contain a chiral carbon atom.
  • the optically active amino acids are of the L-configuration.
  • any of the amino acids of the A 1 or A 12 group can be of the D- or L-configuration.
  • peptides written out herein is such that the amino terminal end is on the left side of the chain and the carboxy terminal end is on the right side of the chain.
  • a three-letter code begining with an upper case letter indicates the L-confuguration and a three-letter code beginning with a lower-case letter indicates the D-configuration.
  • polypeptides of formula 1 can form pharmaceutically acceptable salts with any non-toxic, organic or inorganic acid.
  • inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric and phosphoric acid and acid metal salts such as sodium
  • organic acids which form suitable salts include the mono, di and tricarboxylic acids.
  • organic acids which form suitable salts are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
  • Salts of the carboxy terminal amino acid moiety include the non-toxic carboxylic acid salts formed with any suitable inorganic or organic bases.
  • these salts include those of alkali metals, for example, sodium and potassium;
  • alkaline earth metals such as calcium and magnesium
  • light metals of Group IIIA including aluminum
  • organic radicals such as calcium and magnesium
  • primary, secondary and tertiary amines as for example, trialkylamines, including triethylamine, procaine,
  • certain compounds of formula 1 additionally possess significant antiplatelet activity.
  • q and r are each an integer of from 1 to 5 or wherein A 1 is a peptide fragment containing from 3 to 11 residues wherein the carboxy terminal end of the peptide fragment is a dipeptide fragment of formula 5 or 6 are platelet aggregation inhibitors.
  • a 1 is Thr-Pro-Lys-Arg-Gln-Thr-Ser-Gly-Pro-,
  • a 2 is preferably a group of the formula
  • n is an integer of from 1 to 5 and wherein R' 2 ' is an H or a (C 1 -C 4 ) alkyl group;
  • a 12 a bond, Glu, glu or -Glu-Gln;
  • a 2 is Asp
  • a 5 Glu or Pro
  • a 6 Phe or Cha
  • a 2 is preferably a group of the formula
  • n is an integer of from 1 to 5 and wherein is an H or a (C 1 -C 4 )alkyl group;
  • a 12 a bond or -Glu-Gln-;
  • peptide analogs of this invention can be prepared by a variety of procedures readily known to those skilled in the art. Such procedures include the solid phase sequential and block synthesis, gene cloning and
  • ⁇ -amino protected amino acid is bound to a resin support.
  • the resin support employed can be any suitable resin conventionally employed in the art for the solid phase preparation of polypeptides, preferably polystyrene which has been cross-linked with from 0.5 to about 3 percent divinyl benzene, which has been either chloromethylated or hydroxymethylated to provide sites for ester formation with the initially introduced ⁇ -amino protected amino acid.
  • a tert-butyloxycarbonyl (Boc) protected Thr bound to a benzylated, hydroxymethylated phenylacetamidomethyl (PAM) resin can be used and is commercially available.
  • the protecting group is removed using any suitable procedure such as by using trifluoro- acetic acid in methylene chloride, trifluoroacetic acid alone, or HCl in dioxane. The deprotection is carried out at a temperature of between 0°C and room temperature.
  • the ⁇ -amino protecting group employed with each amino acid introduced into the polypeptide sequence may be any such protecting group known to the art.
  • acyl type protecting groups such as: formyl, trifluoroacetyl,
  • benzyloxycarbonyl such as p-chlorobenzyloxycarbonyi, p-nitrobenzyl- carbonyl, p-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, ⁇ , ⁇ -dimethyl-3,5-dimethoxybenzyloxycarbonyl and benzhydryloxycarbonyl; (3) aliphatic urethan protecting groups such as tert-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl,isopropyloxycarbonyl, ethoxycarbonyl and allyloxycarbonyl; (4) cycloalkyl urethan type protecting groups such as cyclopentyloxycarbonyl, adamantyloxycarbonyl and cyclohexyloxycarbonyl; (5) thio urethan type protecting groups such as phenyl
  • the preferred ⁇ -amino protecting group is tert-butyloxycarbonyl.
  • Other coupling agents are (1) carbodiimides (e.g., N,N'-dicyclohexylcarbodiimide and N-ethyl-N'-( ⁇ -dimethylaminopropylcarbodiimide); (2) cyanamides (e.g., N,N-dibenzylcyanamide); (3) ketenimines;
  • isoxazolium salts e.g., N-ethyl-5-phenyl-isoxazolium-3'-sulfonate; (5) monocyclic nitrogen containing heterocyclic amides of aromatic character containing one through four nitrogens in the ring such as imidazolides, pyrazolides, and 1,2,4-triazolides.
  • Specific heterocyclic amides that are useful include N,N'-carbonyldiimidazole and N,N-carbonyl-di-1,2,4-triazole; (6) alkoxylated acetylene
  • reagents which form a mixed anhydride with the carboxyl moiety of the amino acid e.g., ethylchloroformate and isobutylchloroformate
  • the symmetrical anhydride of the amino acid to be coupled e.g., ethylchloroformate and isobutylchloroformate
  • Each protected amino acid or amino acid sequence is introduced into the solid phase reactor in about a fourfold excess and the coupling is carried out in a medium of dimethylformamide: methylene chloride (1:1) or in
  • the peptide is removed from the resin. This can be done by hydrolysis such as by treatment of the resin bound polypeptide with a solution of dimethyl sulfide, p-cresol and thiocresol in dilute aqueous hydrofluoric acid.
  • side chain protecting group is critical in that it must be one which is not removed by cleavage during cleavage of the protecting group of the ⁇ -amino moiety.
  • suitable side chain protecting groups for lysine are benzyloxycarbonyl and substituted
  • benzyloxycarbonyl said substituent being selected from halo (e.g., chloro, bromo, fluoro) and nitro (e.g., 2-chlorobenzyloxycarbonyl, p-nitrobenzyloxy-carbonyl, 3,4-dichlorobenzyloxycarbonyl), tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl and diisopropylmethoxycarbonyl.
  • halo e.g., chloro, bromo, fluoro
  • nitro e.g., 2-chlorobenzyloxycarbonyl, p-nitrobenzyloxy-carbonyl, 3,4-dichlorobenzyloxycarbonyl
  • tosyl t-amyloxycarbonyl, t-butyloxycarbonyl and diisopropylmethoxycarbonyl.
  • the alcoholic hydroxyl group of threonine and serine can be protected with an acetyl, benzoyl, tert-butyl, trityl, benzyl, 2,6-dichlorobenzyl or benzyloxycarbonyl group.
  • the preferred protecting group is benzyl.
  • These groups can be removed by procedures well known in the art. Typically protecting group removal is done after the peptide chain synthesis is complete but the protecting groups can be removed at any other appropriate time.
  • the anticoagulant and antiplatelet dose of a peptide analog of this invention is from 0.2 mg/kg to 250 mg/kg of patient body weight per day depending on the patient, the severity of the thromobotic condition to be treated and the peptide analog selected.
  • Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease as well as for the treatment of, for example, coronary
  • Antiplatelet therapy is indicated for the prevention of reoccurance of myocardial infarction and stroke. Those experienced in this field are readily aware of the circumstances requiring anticoagulant and antiplatelet therapy. The term
  • patient used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice. Although some of the peptide derivatives may survive passage through the gut following oral administration, applicants prefer non-oral administration, for example, subcutaneous, intravenous, intramuscular or intraperitoneal; administration by depot injection; by implant preparation; or by application to the mucous membranes, such as , that of the nose , throat and bronchial tubes , for example, in an aerosol can containg a peptide derivative of this invention in a spray or dry powder form.
  • the compounds may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically
  • a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically
  • oils which can be employed in these preparations are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, and mineral oil.
  • polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • the compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
  • Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber manufactured by the Dow-Corning Corporation.
  • the peptide was synthesized by solid-phase methods using 0.1 mmol of a 0.66 mmol/g Boc-Gln-PAM resin. Double symmetrical anhydride couplings were performed with 2.0 mmol N ⁇ -Boc-amino acid (Peptides International). The side chain protection utilized was: Asp(Chx),Ser (Bzl), Glu(Bzl). Upon completion of the synthesis the N ⁇ -Boc protection was removed with 50% trifluoroacetic acid in methylene
  • the peptide was purified by desalting on a 92 ⁇ 2.6 cm Sephadex G-15 column in 5% aqueous acetic acid and

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Separation Of Suspended Particles By Flocculating Agents (AREA)

Abstract

Cette invention concerne des dérivés de peptides qui sont des agents anticoagulants utiles.
EP91913182A 1990-07-24 1991-06-28 Peptides anticoagulants Expired - Lifetime EP0540574B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US55728890A 1990-07-24 1990-07-24
PCT/US1991/004658 WO1992001710A1 (fr) 1990-07-24 1991-06-28 Peptides anticoagulants
US557288 2009-09-10

Publications (3)

Publication Number Publication Date
EP0540574A1 true EP0540574A1 (fr) 1993-05-12
EP0540574A4 EP0540574A4 (fr) 1994-04-27
EP0540574B1 EP0540574B1 (fr) 1996-09-11

Family

ID=24224803

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91913182A Expired - Lifetime EP0540574B1 (fr) 1990-07-24 1991-06-28 Peptides anticoagulants

Country Status (15)

Country Link
US (1) US5495000A (fr)
EP (1) EP0540574B1 (fr)
JP (1) JP3111075B2 (fr)
KR (1) KR100195424B1 (fr)
AT (1) ATE142648T1 (fr)
AU (1) AU648096B2 (fr)
CA (1) CA2086243C (fr)
DE (1) DE69122103T2 (fr)
DK (1) DK0540574T3 (fr)
ES (1) ES2094228T3 (fr)
FI (1) FI930265A (fr)
GR (1) GR3021660T3 (fr)
HU (1) HUT63180A (fr)
NO (1) NO930234L (fr)
WO (1) WO1992001710A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7109326B2 (en) 1997-04-15 2006-09-19 Genentech, Inc. Halo-alkoxycarbonyl prodrugs

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2605586B2 (ja) * 1992-07-24 1997-04-30 トヨタ自動車株式会社 内燃機関の排気浄化装置
JP2009510105A (ja) 2005-09-28 2009-03-12 バイオバスキュラー インコーポレーティッド 血小板および細胞の接着、細胞移動、および炎症を阻止するための方法および組成物
US20110034396A1 (en) * 2005-09-28 2011-02-10 Biovascular, Inc. Methods and compositions for inhibiting cell migration and treatment of inflammatory conditions
CN103520160B (zh) * 2013-10-17 2015-04-22 广东药学院 三棱中肽类化合物的应用
KR102152135B1 (ko) * 2018-11-29 2020-09-04 글라드아이 주식회사 음료용기
KR102152140B1 (ko) * 2019-10-21 2020-09-04 글라드아이 주식회사 음료용기
CN112430254B (zh) * 2020-11-25 2021-10-26 广东海洋大学 一种抗凝血活性肽衍生物及其制备方法和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0347376A2 (fr) * 1988-06-11 1989-12-20 Ciba-Geigy Ag Polypeptides à activité anticoagulante

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US4792525A (en) * 1982-08-04 1988-12-20 La Jolla Cancer Research Foundation Tetrapeptide
DE3438296A1 (de) * 1984-04-18 1985-11-07 Hoechst Ag, 6230 Frankfurt Neue polypeptide mit blutgerinnungshemmender wirkung, verfahren zu deren herstellung bzw. gewinnung, deren verwendung und diese enthaltende mittel
DE3445532A1 (de) * 1984-12-13 1986-06-19 Plantorgan Werk Heinrich G.E. Christensen, KG, 2903 Bad Zwischenahn Hirudin-pa, desulfatohirudine-pa, verfahren zur herstellung und pharmazeutische mittel, die diese wirkstoffe enthalten
CA1341032C (fr) * 1987-01-23 2000-06-20 John L. Krstenansky Peptides anti-coagulants
AU3098289A (en) * 1988-03-04 1989-09-07 Biogen, Inc. Hirudin peptides
FR2628429B1 (fr) * 1988-03-08 1990-12-28 Transgene Sa Variants de l'hirudine, leurs utilisations et les procedes pour les obtenir
NZ228995A (en) * 1988-05-10 1992-03-26 Merrell Dow Pharma Hirudin peptide derivatives and pharmaceutical compositions
IT217993Z2 (it) * 1988-12-15 1992-03-05 Faccia Tiziano Agitatore-miscelatore per impianti di biogas
ZA907743B (en) * 1989-10-03 1991-07-31 Merrell Dow Pharma Radiolabeled anticoagulant peptides
CA2026376C (fr) * 1989-10-03 2002-01-01 John L. Krstenansky Peptides anticoagulants
AU654820B2 (en) * 1990-06-15 1994-11-24 Majesty (Her) In Right Of Canada As Represented By The National Research Council Of Canada Thrombin inhibitors based on the amino acid sequence of hirudin
IT1243358B (it) * 1990-07-23 1994-06-10 Iketon Farmaceutici Srl Composizioni farmaceutiche per la somministrazione orale di irudina
US5118790A (en) * 1990-07-24 1992-06-02 Sri International Analogs of hirudin
ZA915658B (en) * 1990-07-24 1992-05-27 Merrell Dow Pharma Analogs of hirudin having antiplatelet activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0347376A2 (fr) * 1988-06-11 1989-12-20 Ciba-Geigy Ag Polypeptides à activité anticoagulante

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 116, no. 3, 20 January 1992, Columbus, Ohio, US; abstract no. 15343b, J L KRSTENANSKY ET AL. 'Structure-function relationship of the C-terminal functional domain of hirudin and its variants' page 16 ; & BLOOD COAGULATION FIBRINOLYSIS vol. 2, no. 1 , 1991 pages 91 - 96 *
FEBS LETTERS. vol. 269, no. 2 , 3 September 1990 , AMSTERDAM NL pages 425 - 429 J L KRSTENANSKY ET AL. 'The C-terminal binding domain of hirullin P18. Antithrombin activity and comparison to hirudin peptides' *
SCIENCE. vol. 249, no. 3 , 20 July 1990 , LANCASTER, PA US pages 277 - 280 T. J. RYDEL ET AL. 'The structure of a complex of recombinant hirudin and human alpha-thrombin' *
See also references of WO9201710A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7109326B2 (en) 1997-04-15 2006-09-19 Genentech, Inc. Halo-alkoxycarbonyl prodrugs

Also Published As

Publication number Publication date
HU9300191D0 (en) 1993-04-28
EP0540574B1 (fr) 1996-09-11
AU648096B2 (en) 1994-04-14
JPH05508850A (ja) 1993-12-09
HUT63180A (en) 1993-07-28
KR100195424B1 (ko) 1999-06-15
NO930234D0 (no) 1993-01-22
JP3111075B2 (ja) 2000-11-20
ATE142648T1 (de) 1996-09-15
GR3021660T3 (en) 1997-02-28
CA2086243A1 (fr) 1992-01-25
DE69122103T2 (de) 1997-02-13
EP0540574A4 (fr) 1994-04-27
ES2094228T3 (es) 1997-01-16
DE69122103D1 (de) 1996-10-17
US5495000A (en) 1996-02-27
FI930265A0 (fi) 1993-01-22
NO930234L (no) 1993-01-22
AU8221091A (en) 1992-02-18
DK0540574T3 (da) 1996-09-30
FI930265A (fi) 1993-01-22
WO1992001710A1 (fr) 1992-02-06
CA2086243C (fr) 2001-10-02

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